Synthesis and Structure-Activity Relationship of Pyxinol Derivatives as Novel Anti-Inflammatory Agents.

Pyxinol, the main metabolite of 20S-protopanaxadiol in human liver, was chosen as a novel skeleton for the development of anti-inflammatory agents. Pyxinol derivatives modified at C-3, C-12, or C-25 and selected stereoisomers were designed, prepared, and investigated for in vitro anti-inflammatory activities. Structure-activity relationship (SAR), focused on skeleton, was analyzed based on their ability to inhibit lipopolysaccharide (LPS)-induced nitric oxide (NO) synthesis. The preliminary SAR results signified that the biological activity of the pyxinol derivatives is largely dependent on the R/S stereochemistry of pyxinol skeleton and the hydroxy at C-3 is a modifiable position. Among the tested compounds, the 3-oximinopyxinol (4a) exhibited the most potent NO-inhibitory activity and was even comparable to the steroid drug. Furthermore, compound 4a also significantly decreased LPS-induced TNF-α and IL-6 synthesis and iNOS and COX-2 expressions via the NF-κB pathway. This study proves that pyxinol is an interesting skeleton for anti-inflammatory drug discovery.